Synthetic oligonucleotides constitute an important class of compounds which
can exhibit biological activity. As potential drugs they could be employed in antisense
strategy by acting on the pathogenic mRNA, causing inactivation of the target
molecules during the translation process [1]. Ideal antisense agent (ASO) should be
resistant to exo and/or endonucleases, exhibit a suitable pharmacological and pharmacokinetic
profile and exhibits high binding affinity towards the target mRNA. To
improve some properties of the ASO plethora of the chemical modifications introduced
within the nucleobase, sugar unit and internucleotide linkage are investigated
[3]. Among them, phosphorothioate oligonucleotides (PS-oligo), created by replacing
one of the nonbridging oxygen atoms with a sulfur atom, are the major representatives
of DNA analogs. PS-oligo display several attractive features like nuclease
resistance, activation of RNase H, and good pharmacokinetic properties [1].
Replacement of one of two nonbridging oxygens at phosphorus by sulfur induces
asymmetry at the phosphorus atom. Hence, the synthesized oligo(nucleoside
phosphorothioate) is a mixture of 2n diastereomers (where n is the number of internucleotide
phosphorothioate functions). Therefore the actual biological activity of
the P-chiral oligonucleotide analogues, (e.g., interactions with proteins or nucleic
acids) may depend on stereochemical factors [7]. One has to keep in mind that
the phosphoramidite [5] and H-phosphonate [32] methodologies (commonly used
to prepare PS-oligo) are nonstereospecific and give a mixture of 2n diastereomers.
Thus, various methods have been elaborated to synthesize these P-chiral oligonucleotide
analogs in a stereocontrolled manner [15, 17], among them the oxathiaphospholane
method developed by Stec et al. [18], the method utilizing nucleoside
3’-O-(3-N-acyl)oxazaphospholidine derivatives as monomer units [19], and the
method based on a stereoselective synthesis of nucleoside 3’-O-oxazaphospholidine
monomers [21, 22] are the most significant.
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